Evaluation of Molecular Changes Induced by Budesonide in COPD Patients Stratified by Eosinophil Levels

The primary objective of this study is to determine the **molecular changes** associated with the use of inhaled corticosteroids (ICS) in patients with **chronic obstructive pulmonary disease (COPD)**, stratified by different blood eosinophil counts. This is clinically relevant as it may help to tailor ICS treatment based on eosinophil levels, potentially improving therapeutic outcomes and minimizing unnecessary exposure to ICS in patients unlikely to benefit.

Secondary objectives include:

• Determining the molecular changes associated with the use of ICS in COPD patients with varying degrees of airflow limitation (FEV1 % ref.).
• Comparing the identified molecular changes with data obtained during exacerbation events in previous studies, by calculating the percentage of enrichment and/or overlap with molecular data from this study.
• Comparing the identified molecular changes with available data from stable COPD patients in previous longitudinal studies, focusing on outcomes such as the number of exacerbations and lung function decline.
• Comparing the data obtained in the 3TR-ICS COPD study with other diseases within the 3TR consortium, including transcriptome, proteins, and epigenome data.
• Determining changes in FEV1 associated with the use of ICS in COPD patients.

The clinical trial involves a total of **30 participants** diagnosed with **chronic obstructive pulmonary disease (COPD)**. The study population includes both male and female subjects aged 40 years and older. Participants are required to have a history of smoking, with a minimum of 10 pack-years, and must be former smokers for at least six months. The trial specifically targets individuals with mild to moderate COPD, as indicated by a post-bronchodilator FEV1/FVC ratio of less than 0.70 and an FEV1 between 30% and 80% of the predicted value. All participants are on a regular treatment regimen with dual long-acting bronchodilators (LABA+LAMA) for a minimum of eight weeks prior to the study. Women of child-bearing potential are included, provided they have a negative pregnancy test and agree to use highly effective contraceptive methods, excluding hormonal contraceptives due to potential adverse effects. The selection process ensures that participants have provided signed written informed consent. The trial does not exclude vulnerable populations, indicating a comprehensive approach to understanding the molecular changes associated with the use of inhaled corticosteroids (ICS) in COPD patients with varying blood eosinophil counts.

The clinical trial is designed to evaluate the **molecular changes** associated with the use of inhaled corticosteroids (ICS) in patients with **chronic obstructive pulmonary disease (COPD)**, stratified by blood eosinophil levels. This study employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to commence on June 3, 2024, and conclude by December 31, 2025, with a total duration of approximately 18 months. Participants will be involved for a maximum of 8 weeks, during which they will receive **budesonide** as the investigational medicinal product, administered via inhalation.

The study will include several key visits: an initial screening visit, followed by two main study visits, and an end-of-study visit. The screening visit will determine eligibility based on criteria such as age, smoking history, and lung function. Eligible participants will be randomized to receive either ICS treatment or usual care. The primary endpoint will assess significant molecular changes in biological samples, calculated as variations from Visit 2 to Visit 3 over the 8-week treatment period. Secondary endpoints will evaluate molecular changes in relation to different severities of airflow limitation.

Participants are expected to adhere to the study protocol, including regular use of dual long-acting bronchodilators (LABA+LAMA) for at least 8 weeks prior to inclusion. Women of child-bearing potential must use highly effective contraceptive methods and have a negative pregnancy test before participation. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or any adverse events that compromise participant safety. The trial is classified as a low-intervention study, with minimal additional risk compared to standard clinical practice.

The clinical trial involves the administration of **BUDESONIDE**, an inhalation powder, as the experimental medication. **BUDESONIDE** is a chemical substance classified as a glucocorticosteroid. The medication is administered via the **inhalation** route. The maximum daily dose is set at 800 µg (micrograms), with a total maximum dose of 44,800 µg over the course of the study. The treatment period is limited to a maximum of 8 weeks. The study aims to evaluate the molecular changes associated with the use of inhaled corticosteroids (ICS) in patients with Chronic Obstructive Pulmonary Disease (COPD) stratified by eosinophil levels.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the source data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial's main objective is to determine the molecular changes associated with the use of ICS in COPD patients with varying blood eosinophil counts.

Efficacy in this clinical trial will be assessed by evaluating significant molecular changes associated with the use of inhaled corticosteroids (ICS) in patients with Chronic Obstructive Pulmonary Disease (COPD), stratified by blood eosinophil levels. The primary endpoint involves measuring molecular changes, such as those in the microbiome, transcriptome, proteins, and epigenetics, in samples including sputum, nasal and oropharyngeal swabs, urine, and blood. These changes will be compared between patients receiving ICS treatment and those receiving usual care without ICS. The assessment will focus on variations observed from Visit 2 to Visit 3, over an 8-week period, with statistical significance determined by p-values less than 0.05 and/or a false discovery rate (FDR) of less than 0.05.

Secondary endpoints will similarly evaluate significant molecular changes in the same types of samples, but will focus on patients with different severities of airflow limitation. The same statistical criteria for significance will apply. The trial aims to identify molecular signatures that correlate with the response to ICS treatment, providing insights into the efficacy of ICS in managing COPD in patients with varying eosinophil levels and airflow limitations. The data collection and analysis will be conducted using validated laboratory tests and methodologies to ensure accuracy and reliability of the results.